Special Issue "Adverse Drug Reactions and Gender Differences"

A special issue of Pharmaceuticals (ISSN 1424-8247).

Deadline for manuscript submissions: 31 December 2021.

Special Issue Editors

Dr. Concetta Rafaniello
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Guest Editor
Department of Experimental Medicine, University of Campania “L. Vanvitelli”, Via Santa Maria di Costantinopoli 16, 80138, Naples, Italy
Interests: pharmacovigilance; pharmacoepidemiology; prescriptive appropriateness and clinical research both pre- and postmarketing
Prof. Annalisa Capuano
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Guest Editor
Department of Experimental Medicine, University of Campania “L. Vanvitelli”, Via Santa Maria di Costantinopoli 16, 80138, Naples, Italy
Interests: pharmacovigilance; pharmacoepidemiology

Special Issue Information

Dear Colleagues,

In the era of personalized and precision medicine, gender differences continue to be a “grey zone” that requires better definition, especially in terms of drug response and tolerability. Many studies have attempt to associate gender difference with a specific drug response or drug toxicity, but more evidence is needed to bridge the gap. In terms of the drug safety profile, several studies suggest that women are more exposed to the risk of adverse drug reaction (ADR) occurrence than men; this difference could be due to a combination of sex differences, such as weight, height, body surface area, fat mass, plasma volume, total amount of body water, biological differences, and hormonal changes, and gender differences, including psychological, behavioral, and/or cultural differences. Therefore, gender and sex differences could result in different drug tolerability in terms of ADR frequency and seriousness. In this context, advances in pharmacology are essential to understand the gender differences associated with pharmacological treatments, with the aim of better defining the mechanisms underlying the differences in responses to drugs that, in turn, influence their tolerability. Considering that all women are still phased out from clinical trials, evidence from real world data is an important tool for identifying the true safety profiles of medicinal products in populations that have not been adequately studied, in order to promote gender-oriented and appropriate drug prescription. Although the data available regarding the impact of gender on the safety profiles of medicinal products shows a prevalence of ADR occurrence amongst females over males, gender-specific pharmacovigilance activities must be undertaken in order to reduce the risks associated with the use of medicinal products and to conduct a risk/benefit assessment in greater detail to elucidate the differences between men and women in terms of pharmacokinetics and pharmacodynamics.

In this Special Issue, experts are invited to submit clinical trial, experimental, original, and review articles that contribute to improving the understanding of the different drug safety profiles related to gender differences.

Dr. Concetta Rafaniello
Prof. Annalisa Capuano
Guest Editors

Manuscript Submission Information

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Keywords

  • gender differences
  • adverse drug reaction
  • real world data
  • randomized clinical trial

Published Papers (6 papers)

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Research

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Article
Incident Type 2 Diabetes Risk of Selective Estrogen Receptor Modulators in Female Patients with Breast Cancer
Pharmaceuticals 2021, 14(9), 925; https://doi.org/10.3390/ph14090925 - 14 Sep 2021
Viewed by 794
Abstract
Accumulating evidence indicates a link between diabetes and cancer. Selective estrogen receptor modulators (SERMs) may increase diabetes risk via antiestrogen effects. This study investigated incident diabetes risk of SERM treatment and its effects on metastatic cancer and death prevention in breast cancer survivors. [...] Read more.
Accumulating evidence indicates a link between diabetes and cancer. Selective estrogen receptor modulators (SERMs) may increase diabetes risk via antiestrogen effects. This study investigated incident diabetes risk of SERM treatment and its effects on metastatic cancer and death prevention in breast cancer survivors. This retrospective cohort study included female patients with early-stage breast cancer, treated with or without SERMs, between 2008 and 2020 in a tertiary care hospital in Korea. Four propensity score-matched comparison pairs were designed: SERM use versus non-use, long-term use (≥1500 days) versus non-use, tamoxifen use versus non-use, and toremifene use versus non-use; then, logistic regression analysis was performed for risk analysis. SERMs in general were not associated with an elevated risk of diabetes; however, when used for ≥1500 days, SERMs—especially toremifene—substantially increased diabetes risk in breast cancer patients (OR 1.63, p = 0.048). Meanwhile, long-term SERM treatment was effective at preventing metastatic cancer (OR 0.20, p < 0.001) and death (OR 0.13, p < 0.001). SERM treatment, albeit generally safe and effective, may increase diabetes risk with its long-term use in women with breast cancer. Further studies are required to verify the association between toremifene treatment and incident diabetes. Full article
(This article belongs to the Special Issue Adverse Drug Reactions and Gender Differences)
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Article
Comparative Safety Profiles of Sedatives Commonly Used in Clinical Practice: A 10-Year Nationwide Pharmacovigilance Study in Korea
Pharmaceuticals 2021, 14(8), 783; https://doi.org/10.3390/ph14080783 - 09 Aug 2021
Viewed by 717
Abstract
This study aims to compare the prevalence and seriousness of adverse events (AEs) among sedatives used in critically ill patients or patients undergoing invasive procedures and to identify factors associated with serious AEs. Retrospective cross-sectional analysis of sedative-related AEs voluntarily reported to the [...] Read more.
This study aims to compare the prevalence and seriousness of adverse events (AEs) among sedatives used in critically ill patients or patients undergoing invasive procedures and to identify factors associated with serious AEs. Retrospective cross-sectional analysis of sedative-related AEs voluntarily reported to the Korea Adverse Event Reporting System from 2008 to 2017 was performed. All AEs were grouped using preferred terms and System Organ Classes per the World Health Organization—Adverse Reaction Terminology. Logistic regression was performed to identify factors associated with serious events. Among 95,188 AEs, including 3132 (3.3%) serious events, the most common etiologic sedative was fentanyl (58.8%), followed by pethidine (25.9%). Gastrointestinal disorders (54.2%) were the most frequent AEs. The most common serious AE was heart rate/rhythm disorders (33.1%). Serious AEs were significantly associated with male sex; pediatrics; etiologic sedative with etomidate at the highest risk, followed by dexmedetomidine, ketamine, and propofol; polypharmacy; combined sedative use; and concurrent use of corticosteroids, aspirin, neuromuscular blockers, and antihistamines (reporting odds ratio > 1, p < 0.001 for all). Sedative-induced AEs are most frequently reported with fentanyl, primarily manifesting as gastrointestinal disorders. Etomidate is associated with the highest risk of serious AEs, with the most common serious events being heart rate/rhythm disorders. Full article
(This article belongs to the Special Issue Adverse Drug Reactions and Gender Differences)
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Article
Risk of Hospitalization for Adverse Drug Events in Women and Men: A Post Hoc Analysis of an Active Pharmacovigilance Study in Italian Emergency Departments
Pharmaceuticals 2021, 14(7), 678; https://doi.org/10.3390/ph14070678 - 15 Jul 2021
Viewed by 748
Abstract
This post hoc analysis of an Italian active pharmacovigilance study describes pharmacological differences of ADEs leading to emergency department (ED) visits and hospitalization in women and men. During the study period (January 2007–December 2018), 61,855 reports of ADEs leading to ED visits were [...] Read more.
This post hoc analysis of an Italian active pharmacovigilance study describes pharmacological differences of ADEs leading to emergency department (ED) visits and hospitalization in women and men. During the study period (January 2007–December 2018), 61,855 reports of ADEs leading to ED visits were collected. Overall, 30.6% of ADEs resulted in hospitalization (30% in women and 31% in men). Multivariate logistic regression showed that, among women, drug classes significantly associated with an increased risk of hospitalization were heparins (ROR 1.41, CI 1.13–176), antidepressants (ROR 1.12, CI 1.03–1.23) and antidiabetics (ROR 1.13, CI 1.02–1.24). Among men, only vitamin K antagonists (ROR 1.28, CI 1.09–1.50), opioids (ROR 1.30, CI 1.06–1.60) and digitalis glycosides (ROR 1.32, CI 1.09–1.59) were associated with a higher risk of hospitalization. Overall, older age, multiple suspected drugs and the presence of comorbidities were significantly associated with a higher risk of hospitalization. A significantly reduced risk of hospitalization was observed in both women and men experiencing an adverse event following immunization (ROR 0.36, CI 0.27–0.48 and 0.83, 0.42–0.74, respectively) compared to drugs. Results obtained from this real-world analysis highlight important aspects of drug safety between sexes. Full article
(This article belongs to the Special Issue Adverse Drug Reactions and Gender Differences)
Article
Cardiac Events Potentially Associated to Remdesivir: An Analysis from the European Spontaneous Adverse Event Reporting System
Pharmaceuticals 2021, 14(7), 611; https://doi.org/10.3390/ph14070611 - 25 Jun 2021
Cited by 2 | Viewed by 939
Abstract
Remdesivir was recommended for hospitalized patients with COVID-19. As already reported in the Summary of Product Characteristics, most of remdesivir’s safety concerns are hepatoxicity and nephrotoxicity related. However, some cases have raised concerns regarding the potential cardiac events associated with remdesivir; therefore, the [...] Read more.
Remdesivir was recommended for hospitalized patients with COVID-19. As already reported in the Summary of Product Characteristics, most of remdesivir’s safety concerns are hepatoxicity and nephrotoxicity related. However, some cases have raised concerns regarding the potential cardiac events associated with remdesivir; therefore, the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency requested to investigate all available data. Therefore, we analyzed all Individual Case Safety Reports (ICSRs) collected in the EudraVigilance database focusing on cardiac adverse events. From April to December 2020, 1375 ICSRs related to remdesivir were retrieved from EudraVigilance, of which 863 (62.8%) were related to male and (43.3%) adult patients. A total of 82.2% of all AEs (N = 2604) was serious and one third of the total ICSRs (N = 416, 30.3%) had a fatal outcome. The most frequently reported events referred to hepatic/hepatobiliary disorders (19.4%,), renal and urinary disorders (11.1%) and cardiac events (8.4%). Among 221 cardiac ICSRs, 69 reported fatal outcomes. Other drugs for cardiovascular disorders were reported as suspected/concomitant together with remdesivir in 166 ICSRs (75.1%), 62 of which were fatal. Moreover, the mean time to overall cardiac event was 3.3 days (±2.2). Finally, disproportionality analysis showed a two-fold increased risk of reporting a cardiac adverse event associated with remdesivir compared to both hydroxychloroquine and azithromycin. This study showed that remdesivir could be associated to risk of cardiac events, suggesting a potential safety signal which has not been completely evaluated yet. Further studies are needed to confirm these findings. Full article
(This article belongs to the Special Issue Adverse Drug Reactions and Gender Differences)
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Article
Signal Detection of Adverse Drug Reactions of Cephalosporins Using Data from a National Pharmacovigilance Database
Pharmaceuticals 2021, 14(5), 425; https://doi.org/10.3390/ph14050425 - 02 May 2021
Cited by 1 | Viewed by 761
Abstract
This case-non-case study aims to detect signals not currently listed on cephalosporin drug labels. From 2009 to 2018, adverse event (AE) reports concerning antibacterial drugs (anatomical therapeutic chemical (ATC) code J01) in the Korea Adverse Events Reporting System (KAERS) database were examined. For [...] Read more.
This case-non-case study aims to detect signals not currently listed on cephalosporin drug labels. From 2009 to 2018, adverse event (AE) reports concerning antibacterial drugs (anatomical therapeutic chemical (ATC) code J01) in the Korea Adverse Events Reporting System (KAERS) database were examined. For signal detection, three indices of disproportionality, proportional reporting ratio (PRR), reporting odds ratio (ROR), and information component (IC), were calculated. The list of signals was compared with ADRs on the drug labels from the United States, United Kingdom, Japan, and South Korea. A total of 163,800 cephalosporin–AE combinations and 72,265 all other J01–AE combinations were analyzed. This study detected 472 signals and 114 new signals that are not included on the drug labels. Cefatrizine–corneal edema (PRR, 440.64; ROR, 481.67; IC, 3.84) and cefatrizine–corneal ulceration (PRR, 346.22; ROR, 399.70; IC, 4.40) had the highest PRR, ROR, and IC among all signals. Additionally, six serious AEs that were not listed on drug labels such as cefaclor-induced stupor (ten cases) and cefaclor-induced respiratory depression (four cases) were found. Detecting signals using a national pharmacovigilance database is useful for identifying unknown ADRs. This study identified signals of cephalosporins that warrant further investigation. Full article
(This article belongs to the Special Issue Adverse Drug Reactions and Gender Differences)

Review

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Review
Just a Reflection: Does Drug Repurposing Perpetuate Sex-Gender Bias in the Safety Profile?
Pharmaceuticals 2021, 14(8), 730; https://doi.org/10.3390/ph14080730 - 27 Jul 2021
Cited by 1 | Viewed by 690
Abstract
Vaccines constitute a strategy to reduce the burden of COVID-19, but the treatment of COVID-19 is still a challenge. The lack of approved drugs for severe COVID-19 makes repurposing or repositioning of approved drugs a relevant approach because it occurs at lower costs [...] Read more.
Vaccines constitute a strategy to reduce the burden of COVID-19, but the treatment of COVID-19 is still a challenge. The lack of approved drugs for severe COVID-19 makes repurposing or repositioning of approved drugs a relevant approach because it occurs at lower costs and in a shorter time. Most preclinical and clinical tests, including safety and pharmacokinetic profiles, were already performed. However, infective and inflammatory diseases such as COVID-19 are linked with hypoalbuminemia and downregulation of both phase I and phase II drug-metabolizing enzymes and transporters, which can occur in modifications of pharmacokinetics and consequentially of safety profiles. This appears to occur in a sex- and gender-specific way because of the sex and gender differences present in the immune system and inflammation, which, in turn, reflect on pharmacokinetic parameters. Therefore, to make better decisions about drug dosage regimens and to increases the safety profile in patients suffering from infective and inflammatory diseases such as COVID-19, it is urgently needed to study repurposing or repositioning drugs in men and in women paying attention to pharmacokinetics, especially for those drugs that are previously scarcely evaluated in women. Full article
(This article belongs to the Special Issue Adverse Drug Reactions and Gender Differences)
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